iabetes mellitus (DM) and metabolic syndrome frequently result in congestive heart failure (CHF) with either preserved or unpreserved left ventricular (LV) systolic function, independent of coronary atherosclerosis. 1,2 This is because insulin resistance (IR) and impaired glucose metabolism facilitate not only coronary atherosclerosis leading to coronary events, but also myocardial interstitial fibrosis 3 and coronary microangiopathy, 4,5 at least partly through nitric oxide (NO)/superoxide imbalance. 2,4 In this regard, new-onset DM during medical treatment of hypertensive patients was reported to significantly increase the risk of cardiovascular events, including CHF, during a long-term follow-up period. 6 Therefore, attention should be paid to the influence of cardiovascular agents on glycemic control during prevention of cardiovascular diseases.The hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have been widely prescribed to reduce cardiovascular events, based on the results of several clinical trials in which lower lipid levels were related to lower coronary event rates. 7-9 Intensive lipid-lowering therapy with atorvastatin (AS) can stop 10 or reverse 11 the further progression of coronary plaques and shows greater prevention of recurrent coronary events after acute coronary syndrome, compared with standard lipid lowering by pravastatin (PS). 9 Thus, the benefit of intensive lipid lowering to prevent coronary events by stabilizing coronary plaques has been established. However, the effects of statin therapy on glycemic control [12][13][14][15][16][17][18][19][20] or on the development of CHF have not been fully investigated and remain controversial. We have recently shown that early and long-term treatment with PS eliciting moderate lipid-lowering effects can retard the development of DM and progression of LV diastolic dysfunction, 15 a manifestation of diabetic cardiomyopathy, in a model of spontaneously developing type II DM, the Otsuka Long-Evans Tokushima Fatty (OLETF) rats. 21 However, whether intensive lipid lowering by other statins can exert greater or similar effects remains unknown. Moreover, although adipocytokines [22][23][24] have been emerging as factors affecting IR and should play an important role in the development of DM, the effects of statin therapy on them also remain to be studied.Therefore, in this study, we compared intensive lipid Background Controversy exists regarding the effects of statin therapy on progressive insulin resistance (IR) and its consequences, in the present study a rat model of spontaneously developing type II diabetes mellitus (DM) was used to examine the impact of atorvastatin (AS) vs pravastatin (PS).
Methods and ResultsThe Otsuka Long-Evans Tokushima Fatty rats were either untreated or treated with 100 mg/kg per day of AS or PS from 6 weeks of age for 24 weeks. AS achieved much greater lipid lowering than PS. Serial oral glucose tolerance tests revealed new-onset diabetes was delayed by PS only. The untreated rats exhibited a progressive decrea...
Hypertension and dyslipidemia frequently coexist in patients with progressive insulin resistance and thus constitute metabolic syndrome. We sought to determine the merits of combining an angiotensin II receptor blocker and a 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor in treating this pathological condition. Five-week-old Otsuka Long-Evans Tokushima Fatty rats, a model of metabolic syndrome, were untreated or treated with olmesartan 3 mg kg À1 per day, pravastatin 30 mg kg À1 per day or their combination for 25 weeks. Long-Evans Tokushima Otsuka rats served as normal controls. The antihypertensive effect of olmesartan and the lipid-lowering properties of pravastatin were both augmented by the combination. The oral glucose tolerance test revealed that only the combined treatment significantly reduced the area under the time-glucose curve, which was accompanied by augmented adiponectin messenger RNA expression in epididymal adipose tissue. Although the total cardiac endothelial nitric oxide synthetase (eNOS) content did not significantly differ among the groups, the combined treatment significantly increased the content of dihydrofolate reductase, a key eNOS coupler. Dihydroethidium staining of the aorta showed that the combination most significantly attenuated superoxide production. Moreover, Azan-Mallory staining revealed that the combination most significantly limited the perivascular fibrosis and wall thickening of intramyocardial coronary arteries. In conclusion, the combination of olmesartan and pravastatin augmented adiponectin expression in white adipose tissue and improved glucose tolerance in a rat model of metabolic syndrome, which was associated with more significant ameliorations of cardiovascular redox state and remodeling than those by treatments with either agent alone.
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